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Chiral 3,3-disubstituted isoindoline-1-one derivative, synthesis method and applications thereof

A technology of isoindoline and synthesis method, which is applied in the directions of drug combination, organic chemistry, organic chemistry, etc., can solve the problems of difficult control of selectivity, lack of catalyst, low activity of substrate, etc., and achieves high atom economy, high Selective, high-yield effects

Inactive Publication Date: 2018-08-10
EAST CHINA NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Due to low substrate activity, lack of catalyst, difficult control of selectivity, and use of toxic carbon monoxide gas, etc., the existing synthetic methods have the disadvantages of high cost, low yield, and cumbersome operation.

Method used

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  • Chiral 3,3-disubstituted isoindoline-1-one derivative, synthesis method and applications thereof
  • Chiral 3,3-disubstituted isoindoline-1-one derivative, synthesis method and applications thereof
  • Chiral 3,3-disubstituted isoindoline-1-one derivative, synthesis method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] 3-p-methoxyphenyl-3-hydroxyisoindolin-1-one (0.4mmol), rhodium acetate (0.01mmol), chiral phosphoric acid and Molecular sieves (0.2g) were dissolved in dichloromethane (1.5mL), then methyl phenyldiazoacetate (0.6mmol) and o-methoxybenzyl alcohol (0.6mmol) dissolved in dichloromethane (1.0ml) ) was added dropwise to the reaction system within 2 hours, and the reaction system was at -20~0°C. After the dropwise addition was completed, it was stirred for 30 minutes, and the solvent was removed under reduced pressure to obtain a crude product whose structure was shown in formula (4a). The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:10~1:3) to obtain a pure product. The yield was 65%, syn:anti=53:47, ee%=93% (syn) / 90% (anti). nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 1 As shown, the HPLC spectrum is as Figure 17 shown.

[0067] syn-4a: 1 H NMR (400MHz, CDCl 3 )δ8.11(d,J=7.8Hz,1H),7.64(d,J=7.4Hz,1H),7.52...

Embodiment 2

[0076]

[0077] 3-p-methoxyphenyl-3-hydroxyisoindolin-1-one (0.4mmol), rhodium acetate (0.01mmol), chiral phosphoric acid and Molecular sieves (0.2g) were dissolved in dichloromethane (1.5mL), then methyl p-chlorophenyldiazoacetate (0.6mmol) and o-methoxybenzyl alcohol ( 0.6mmol) was added dropwise in the reaction system within 2 hours, and the reaction system was at -20~0°C. After the dropwise addition was completed, it was stirred for 30 minutes, and the solvent was removed under reduced pressure to obtain a crude product, whose structure was as shown in formula (4b). Show. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:10~1:3) to obtain a pure product. The yield was 70%, syn:anti=54:46, ee%=89% (syn) / 93% (anti). nuclear magnetic resonance 1 H NMR, 13 C NMR spectrum as figure 2 As shown, the HPLC spectrum is as Figure 18 shown.

[0078] syn-4b: 1 H NMR (400MHz, CDCl3) δ8.11 (d, J = 7.8Hz, 1H), 7.65 (d, J = 7.4Hz, 1H), ...

Embodiment 3

[0088] 3-p-methoxyphenyl-3-hydroxyisoindolin-1-one (0.4mmol), rhodium acetate (0.01mmol), chiral phosphoric acid and Molecular sieves (0.2g) were dissolved in dichloromethane (1.5mL), then methyl p-bromophenyldiazoacetate (0.6mmol) and o-methoxybenzyl alcohol ( 0.6mmol) was added dropwise to the reaction system within 2 hours, and the reaction system was at -20~0°C. After the dropwise addition was completed, it was stirred for 30 minutes, and the solvent was removed under reduced pressure to obtain a crude product, whose structure was as shown in formula (4c). Show. The crude product was subjected to column chromatography (ethyl acetate:petroleum ether=1:10~1:3) to obtain a pure product. The yield was 78%, syn:anti=45:55, ee%=78% (syn) / 91% (anti). nuclear magnetic resonance 1 HNMR, 13 C NMR spectrum as image 3 As shown, the HPLC spectrum is as Figure 19 shown.

[0089] syn-4c: 1 H NMR (400MHz, CDCl3) δ8.10 (d, J = 7.8Hz, 1H), 7.66 (d, J = 7.4Hz, 1H), 7.56–7.46 (m, 1...

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Abstract

The invention discloses a chiral 3,3-disubstituted isoindoline-1-one derivative and a synthesis method thereof. According to the analysis method, a diazo compound, a 3-hydroxyisoindoline-1-one and a benzyl alcohol are used as raw materials, a metal Lewis acid and chiral phosphoric acid are used as catalysts, and a one-step reaction is performed in an organic solvent at a temperature of -20-0 DEG Cby using a molecular sieve defined in the specification as water absorbing agent to obtain the chiral 3,3-disubstituted isoindoline-1-one derivative. According to the present invention, the synthesismethod has advantages of efficient atomic economy, high selectivity, low catalyst consumption, simple and safe operation and the like, and the synthesized chiral 3,3-disubstituted isoindoline-1-one derivative is the important chemical and pharmaceutical intermediate.

Description

technical field [0001] The invention belongs to the fields of synthetic medicine and chemical industry, and mainly relates to a chiral 3,3-disubstituted isoindolin-1-one derivative and its synthesis method and application. Background technique [0002] Chiral 3,3-disubstituted isoindolin-1-one derivatives have good biological activity and are an important skeleton structure for building natural products and drugs, and are important intermediates in organic synthesis and drug synthesis. Chiral 3,3-disubstituted isoindolin-1-ones can also be used to synthesize many anti-tumor drugs, cardiovascular disease and rheumatoid arthritis drugs, etc. Due to low substrate activity, lack of catalyst, difficult control of selectivity, use of poisonous carbon monoxide gas, etc., the existing synthetic methods have the disadvantages of high cost, low yield and cumbersome operation. Contents of the invention [0003] The present invention overcomes the shortcomings existing in the prior a...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/46A61P35/00
CPCC07B2200/07C07D209/46
Inventor 胡文浩寿家毅康正辉张丹
Owner EAST CHINA NORMAL UNIV
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